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首页> 外文期刊>Oncogene >Tp53 deletion in B lineage cells predisposes mice to lymphomas with oncogenic translocations
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Tp53 deletion in B lineage cells predisposes mice to lymphomas with oncogenic translocations

机译：B谱系细胞中Tp53缺失使小鼠易患致癌性易位的淋巴瘤

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Inactivating Tp53 mutations are frequent genetic lesions in human tumors that harbor genomic instability, including B lineage lymphomas with IG translocations. Antigen receptor genes are assembled and modified in developing lymphocytes by RAG/AID-initiated genomic rearrangements that involve the induction of DNA double strand breaks (DSBs). Although TP53 inhibits the persistence of DSBs and induces apoptosis to protect cells from genomic instability and transformation, the development of spontaneous tumors harboring clonal translocations has not been reported in mice that only lack wild-type Tp53 protein or express Tp53 mutants. Tp53 -deficient (Tp53 ~(鈭?鈭?/sup>) mice succumb to T lineage lymphomas lacking clonal translocations but develop B lymphoid tumors containing immunoglobulin (Ig) translocations upon combined inactivation of DSB repair factors, RAG mutation or AID overexpression; mice expressing apoptosis-defective Tp53 mutants develop B cell lymphomas that have not been characterized for potential genomic instability. As somatic rather than germline inactivating mutations of TP53 are typically associated with human cancers and Tp53 deletion has cellular context dependent effects upon lymphocyte transformation, we generated mice with conditional Tp53 deletion in lineage-committed B lymphocytes to avoid complications associated with defective Tp53 responses during embryogenesis and/or in multi-lineage potential cells and, thereby, directly evaluate the potential physiological role of Tp53 in suppressing translocations in differentiated cells. These mb1-cre:Tp53 ~(flox/flox ) mice succumbed to lymphoid tumors containing Ig gene rearrangements and immunophenotypes characteristic of B cells from various developmental stages. Most mb1-cre:Tp53 ~(flox/flox ) tumors harbored clonal translocations, including Igh/c-myc or other oncogenic translocations generated by the aberrant repair of RAG/AID-generated DSBs. Our data indicate that Tp53 serves critical functions in B lineage lymphocytes to prevent transformation caused by translocations in cell populations experiencing physiological levels of RAG/AID-initiated DSB intermediates, and provide evidence that the somatic TP53 mutations found in diffuse large B-cell lymphoma and Burkitt's lymphoma may contribute to the development of these human malignancies.
机译：失活的Tp53突变是人类肿瘤中常见的遗传损伤，具有基因组不稳定性，包括具有IG易位的B谱系淋巴瘤。通过RAG / AID启动的基因组重排，涉及DNA双链断裂（DSBs）的诱导，在发育中的淋巴细胞中组装并修饰抗原受体基因。尽管TP53抑制DSB的持久性并诱导凋亡以保护细胞免受基因组不稳定和转化的影响，但在仅缺乏野生型Tp53蛋白或表达Tp53突变体的小鼠中，尚未报道具有克隆易位的自发性肿瘤的发展。 Tp53缺陷型（ Tp53〜（Δp鈭α/ sup>））小鼠死于缺乏克隆易位的T谱系淋巴瘤，但在联合灭活DSB修复后发展为含有免疫球蛋白（ Ig）易位的B淋巴瘤因子，RAG突变或AID过度表达;表达凋亡缺陷型Tp53突变体的小鼠会发展出B细胞淋巴瘤，但尚未鉴定出潜在的基因组不稳定性。TP53的体细胞失活突变而非种系失活突变通常与人类癌症和> Tp53缺失对淋巴细胞转化具有细胞背景依赖性作用，我们在谱系定型的B淋巴细胞中产生了有条件的 Tp53缺失的小鼠，以避免在胚胎发生过程中和/或在多谱系潜在细胞中与缺陷性Tp53反应相关的并发症，因此，它们直接评估了Tp53在抑制分化细胞中易位的潜在生理作用，这些mb1-cre：Tp53〜（flox / flox）小鼠死于包含不同发展阶段的B细胞特有的Ig基因重排和免疫表型的淋巴样肿瘤。大多数mb1-cre：Tp53〜（flox / flox）肿瘤具有克隆易位，包括Igh / c-myc或RAG / AID产生的DSB异常修复所产生的其他致癌易位。我们的数据表明，Tp53在B谱系淋巴细胞中起关键作用，以防止由经历RAG / AID引发的DSB中间体生理水平的细胞群体易位引起的转化，并提供证据证明在弥漫性大B-细胞中发现的体细胞TP53突变。细胞淋巴瘤和伯基特淋巴瘤可能有助于这些人类恶性肿瘤的发展。

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